1.4- Diazines Diels-Alder reactions

A thermal intramolecular allene 1,2-diazine Diels-Alder reaction proceeded at 160 °C to afford indole derivatives [158],... 

Marcelis A. T. M., van der Plas H. C. Diels-Alder Reactions of Diazines and Pyridines Trends Eleterocycl. Chem. 1990 1 111-123... 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

Pyrroles, indoles and benzo[ft]thiophene act as good dienophiles in inverse electron demand Diels-Alder reactions with 1,2-diazines, 1,2,4-triazines and sy/n/n-tetrazines. This is examplified by the formation of compounds (189) in excellent yields on interaction of indoles and benzo[c]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (87JOC4610 90JOC3257). There are also many examples of such intramolecular reactions, e.g. (190 — 191). 

Pyrroles are obtained by reduction of 1,2-diazines (80JMC481). This reaction has been used in conjunction with inverse electron demand Diels-Alder reactions to prepare 3,4-disubstituted pyrrole-2, 5-dicarboxylic acid derivatives(Scheme 67). Silyl enol ethers or enamines can also serve as the electron-rich dienophiles thus, silyl ethers of ester enolates give 3-methoxypyrroles (84JOC4405). 

Figure 15.15. Preparation of 1,2-diazines by hetero-Diels Alder reaction. X OR, NR2.

Preparation and Diels-Alder Reaction of a Reactive, Electron-Deficient Heterocyclic Azadiene Dimethyl 1,2,4,5-Tetrazine-3,S-Dicarboxylate. 1,2-Diazine and Pyrrole Introduction. 

Diels-Alder reactions pyrrolesThis azadiene undergoes [4 + 2] cycloaddi-non with unactivated dienophiles to form dimethyl l,2-diazine-3,6-dicarboxylates, hich are reduced by zinc in acetic acid with ring contraction to dimethyl pyrrole-1.5-dicarboxylates. 

Diazine (399) undergoes an intramolecular Diels-Alder reaction (195°C, 135 h) yielding the intermediate (400) which fragments giving a mixture of the isomeric pyranopyridines (401) (40% yield) and (402) (22% yield) (Scheme 8) <89T62il>. In the presence of TFA this reaction proceeds at 72°C and gives heterocycle (402) (85% yield) <89T6519>. 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Diels-Alder reactions 1,2,4-triazines. The electron-deficient azadiene system present in 1 can undergo Diels-Alder reactions with electron-rich dienophiles to give an adduct that loses nitrogen to provide 1,2-diazines. Reactions with imidates (>C=NH) substituted with an active leaving group such as SCH, proceed at moderate temperatures to afford 1,2,4-triazines in high yield (equation I). 

The intramolecular Diels-Alder reaction of 1,2-diazines with an alkyne side chain provides a general synthesis of indolines. The reaction requires a high temperature (200-230°). The most satisfactory solvent is 1,3,5-triisopropylbenzene (b.p. 232-236°). Example ... 

Deuteration of arenes, 206 Deuterium, role in nmr, 243 Dextrorotatory, 70 Diastereomers, 69 conformational, 80 Diastereoselective reactions, 91 Diazine, 458, 460 Diazomethane, 67, 353 Diazonium ions, 409 Diazonium salts, 416 Dicarboxylic acids, 342 Diels-Alder reaction, 154 Dienes, polymerization, 153j summary of chemistry, 154 Dienophile, 154 Dihalides, dehalogenation, 91 Dimethyl sulfoxide (DMSO), 305 Dioxane, 285 Dioxin, 447... 

Thus, the electron-deficient 1,2,4,5-tetrazine 7 reacts smoothly with the electron-rich acetylene 8 in an inverse electron-demand Diels-Alder reaction First, the [4+2] cycloaddition of 7 with 8 takes place and then the formed intermediate 9 loses N2 to provide the symmetrical 1,2-diazine 6. 

Weinreb, S. M., Scola, P. M. N-acyl imines and related hetero dienes in [4+2]-cycloaddition reactions. Chem. Rev. 1989, 89,1525-1534. Marcelis, A. T. M., van der Plas, H. C. Diels-Alder reactions of diazines and pyridines. Trends Heterocycl. Chem. 1990, 1,111-123. 

This approach to 1,2-diazine and pyrrole introduction based on the inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate complements the [4 + 2] cycloaddition reactions of a range of electron-deficient heterocyclic azadienes which permits the divergent preparation of a range of heterocyclic agents employing a common dienophile precursor, Scheme I. 

PREPARATION AND DIELS-ALDER REACTION OF A REACTIVE, ELECTRON-DEFICIENT HETEROCYCLIC AZADIENE DIMETHYL 1,2,4,5-TETRAZINE-3,6-DICARBOXYLATE. 1,2-DIAZINE AND PYRROLE INTRODUCTION... 

Diels-Alder Reactions of Dimeth/11,2,4,5-Tetrazine-3,6-dicart)oxylate 1,2-Diazine Introduction ... 

Probably the most useful and general reaction of all these systems is the inverse-electron-demand Diels-Alder reaction with acetylenes (or equivalents) to produce either pyridines or diazines via elimination of hydrogen cyanide, a nitrile or nitrogen. ... 

The reaction is sensitive to the diene/dienophile spacer as well as subtle features apparently important for substrate/product stability under the reaction conditions (200-230°C). Table 10-IV summarizes the intramolecular Diels-Alder reactions of 1,2-diazines. These observations have found application in the total synthesis of the cAMP phosphodiesterase inhibitors PDE-I and PDE-II (24), constituting the central and right-hand segments of the potent antitumor antibiotic CC-1065 [Eq. (17)].76... 

Intramolecular Diels-Alder reactions of unactivated and highly substituted alkenyl74 and alkynyl73 1,2-diazines have been explored [Eq. (16)]. 

Intermolecular Diels-Alder Reactions of Pyrimidines (1,3-Diazines)... 

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